A synthetic route that provides access to chlorin building blocks bearing substituents at the meso- and/or β-positions has recently been described (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172; Balasubramanian, et al. (2000) J. Org. Chem. 65:7919-7929). In addition to selected patterns of functional group handles at the perimeter of the macrocycle, each chlorin bears a geminal dimethyl group to lock in the hydrogenation level yet lacks steric congestion or other unwanted functionality around the reduced ring. The synthesis involves the construction of an Eastern half and a Western half, which are joined to form the chlorin macrocycle in the final step (Scheme 1). This convergent coupling of the Eastern half and Western half is performed in a two-flask procedure involving acid-catalyzed condensation to give a dihydrobilene-α, followed by metal-mediated oxidative cyclization to give the chlorin. The Eastern half, a bromodipyrromethane-monocarbinol, is readily available by the acylation and bromination of a dipyrromethane at the 1- and 9-positions, respectively, followed by reduction. The Western half is a dihydrodipyrrin (1). The Western half has limited stability and generally must be prepared from the stable nitro-hexanone pyrrole precursor and used within a few days.

In our initial search for routes to a suitable Western half, we investigated the synthesis of a tetrahydrodipyrrin via an intermediate tetrahydrodipyrrin N-oxide (comprised of a pyrrole and a pyrroline N-oxide) (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172). The formation of N-oxides by cyclization followed by deoxygenation affords a convenient entry to a number of heterocycles (Katritzky and Lagowski, Chemistry of the Heterocyclic N-Oxides, Academic Press: London and New York, 1971, pp. 166-231; Ochiai, E. Aromatic Amine Oxides, Elsevier: Amsterdam, 1967, pp. 184-209; Albini, A.; Pietra, S. Heterocyclic N-Oxides, CRC Press: Boca Raton, 1991, pp. 120-134). Indeed, pyrroline N-oxides played a central role throughout Todd's studies related to the synthesis of vitamin B12 (Bonnett, et al. (1959) J. Chem. Soc. 2094-2102; Bonnett et al. (1959) J. Chem. Soc. 2102-2104; Bonnett, et al. (1959) J. Chem. Soc. 2105-2108; Brown et al. (1959) J. Chem. Soc. 2109-2116; Brown et al. (1959) J. Chem. Soc. 2116-2122; Clark, et al. (1959) J. Chem. Soc. 2123-2127; Bowering et al. (1963) Annalen 669:106-113; Brown, et al. (1965) J. Chem. Soc. 2337-2340; Brown et al. (1966) Tetrahedron, Suppl. 8, Part 1:15-26; Black, et al. (1976) J. Chem. Soc. Perkin Trans. I (18):1942-1943; Black, et al. (1976) J. Chem. Soc. Perkin Trans. I (18):1944-1950; Black, et al. (1976) J. Chem. Soc. Perkin Trans. I (18):1951-1954; Alderson et al. (1976) J. Chem. Soc. Perkin Trans. I (18):1955-1960). Battersby synthesized a tetrahydrodipyrrin N-oxide, converted it to the corresponding tetrahydrodipyrrin, and upon reaction with a 1-bromo-9-bromomethyldipyrrin in the presence of copper acetate obtained the copper chlorin in 6.9% yield (2.8 mg) (Battersby, et al. (1984) J. Chem. Soc. Perkin Trans. 1 (12):2725-2732). Though Battersby's pyrrole component was substituted with one ester and two alkyl groups, the route employed also proved suitable for our synthesis of a tetrahydrodipyrrin N-oxide incorporating an unsubstituted pyrrole unit (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172). Thus, cyclization of a nitro-hexanone pyrrole (2) afforded the corresponding tetrahydrodipyrrin N-oxide (3), but we were unable to deoxygenate the cyclic nitrone and form the tetrahydrodipyrrin Western half (4) (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172). We resorted to the cyclization of the nitro-hexanone pyrrole 2 with NaOMe/THF followed by TiCl3 in NH4OAc-buffered solution, forming the dihydrodipyrrin 1 directly (without isolating the N-oxide) in yields of 20-30% (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172; Balasubramanian, et al. (2000) J. Org. Chem. 65:7919-7929).